Epidemiological studies suggest that estrogen may protect against age-related cataracts. The discovery of ocular estrogen receptors (ER) indicates that estrogen protection may result from direct interactions with its receptors in the eye. Studies in our transgenic mouse model validate the concept that estrogen is beneficial for the eye; these mice express a repressor (ERdelta3) that inhibits estrogen action, leading to cortical cataract formation. Although the ERalpha and ERbeta protein and/or RNA have been detected in ocular tissues, there has been no confirmation that these receptors are functional, since there are no known estrogen responsive markers in the eye. Therefore, in this proposal, we will use several transgenic mouse models to investigate the function of ERalpha and ERbeta in the lens. Our specific aims will examine 2 critical questions important for understanding the role of estrogen and its receptors in normal lens physiology and cataractogenesis. 1) Can estrogen induce an ER-mediated response directly in the lens? 2) Are both ERalpha and ERbeta essential for maintenance of lens transparency? First, using ERIN transgenic mice, we will determine whether ERalpha, ERbeta, and ERdelta3 receptors can regulate expression of an estrogen responsive reporter gene in the lens. The ERIN model expresses a beta-galactosidase reporter under the control of 2 consensus estrogen response elements (ERE). The alphalERKO and betaERKO mice provide a means to segregate the individual ER subtypes to determine their individual roles in the lens. Therefore, the ERIN mice will be crossbred with alphaERKO, betaERKO, and ERdelta3 transgenic mice to document that each receptor influences estrogen responsive gene expression in the lens. Next, we will investigate if both ERalpha and ERbeta influence spontaneous and ERdelta3-induced cataract development. We will examine aging alphaERKO, betaERKO, and alphabetaERKO mice to determine if loss or each or both receptors induces lens opacity. To ascertain if cataracts occur in our ERdelta3 mouse model due to inhibition of ERalpha and/or ERbeta activity, the ERKO lines will be crossbred with the ERdelta3 mice. These studies will verify that ERalpha, ERbeta, and ERdelta3 are expressed and functional in the lens. In addition, we will establish if both ERalpha and ERbeta have essential roles in preserving lens transparency. The concept that estrogen can provide protection against age-related cataracts is promising. This study will provide the gateway for future studies to investigate how exposure to various estrogens influence risk of age-related cataracts and the potential of estrogens as a therapy for cataract prevention.